WO2011029896A1 - Methods of preparation of muscarinic acetylcholine receptor antagonists - Google Patents
Methods of preparation of muscarinic acetylcholine receptor antagonists Download PDFInfo
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- WO2011029896A1 WO2011029896A1 PCT/EP2010/063290 EP2010063290W WO2011029896A1 WO 2011029896 A1 WO2011029896 A1 WO 2011029896A1 EP 2010063290 W EP2010063290 W EP 2010063290W WO 2011029896 A1 WO2011029896 A1 WO 2011029896A1
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- 0 *CCC(CC1)(CCN1P)C(O*)=O Chemical compound *CCC(CC1)(CCN1P)C(O*)=O 0.000 description 1
- OTUFGRVWNPWRJD-UHFFFAOYSA-N CCOC(C1CCN(CCCl)CC1)=O Chemical compound CCOC(C1CCN(CCCl)CC1)=O OTUFGRVWNPWRJD-UHFFFAOYSA-N 0.000 description 1
- RUJPPJYDHHAEEK-UHFFFAOYSA-N CCOC(C1CCNCC1)=O Chemical compound CCOC(C1CCNCC1)=O RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present application relates to the fields of organic synthesis, and pharmaceutical process chemistry.
- the inventive concept relates to the synthesis of key intermediates useful in the preparation of Muscarinic Acetylcholine Receptor Antagonists (hereinafter “mAChRs”) useful in the treatment of various respiratory diseases and disorders.
- mAChRs Muscarinic Acetylcholine Receptor Antagonists
- Rl is selected from the group consisting of Cl-15 alkyl, halosubstituted Cl-15 alkyl, Cl-15 alkyl cycloalkyl, cycloalkyl, C2-15 alkenyl, hydroxy substituted Cl-15 alkyl, Cl-15 alkyl aryl, Cl-15 alkyl heteroaryl, (CR7R7)qNRaRa, (CR7R7)qNC(0)Ra, (CR7R7)qC(0)NRaRa, (CR7R7)qC(0)Ra, (CR7R7)qOC (O)Ra,
- R2 and R3 are independently selected from the group consisting of aryl, CI -4 alkyl aryl, heteroaryl, CI -4 alkyl heteroaryl, heterocyclic and a CI -4 alkyl heterocyclic moiety, all of which moieties may be optionally substituted; and
- X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
- anion such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
- Reagents and conditions a) l-bromo-2-chloroethane, K 2 C0 3 , acetone; b) LDA, THF; c) R 2 M then R M, THF; d) R1X, ACN, CHC1 3 .
- Ethyl l-(2-chloroethyl)-4-piperidinecarboxylate is prepared by adding l-bromo-2- chloroethane to a solution of commercially available ethyl nipecotate, in acetone, followed by addition of potassium carbonate. This synthesis is illustrated below as Scheme B:
- Example 1 produced a 38.6% yield of the desired Ethyl l-(2-chloroethyl)-4- piperidinecarboxylate product.
- P is a protecting group
- R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl;
- Y is a leaving group.
- Another embodiment of the invention is a process of making compounds of Formula (II)
- P is a protecting group
- R is selected from the group consisting of Q.galkyl, C2-galkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci ⁇ alkyl, aryl, aryl C _
- Y is a leaving group
- P is a protecting group
- R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Q ⁇ alkyl, aryl, aryl C i_4alkyl and heteroaryl C i_4alkyl; a solution of Base, wherein Base is a compound able to deprotonate a weakly acidic C-H bond; and
- step (b) adding to the solution of step (a) a compound of the formula:
- Y is a leaving group
- X is a leaving group; provided that X and Y are different; to yield a compound of Formula (II).
- the present application relates to novel compounds useful as key intermediates in the synthesis of mAChRs as described in WO 2005/104745, which is incorporated by reference herein, and novel methods of preparing these key intermediates.
- P is a protecting group
- R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci_4alkyl, aryl, aryl Q_ 4alkyl and heteroaryl Ci_4alkyl; and Y is a leaving group.
- P is selected from the group of nitrogen protecting groups consisting of N-para- nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), /?-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP) and Tosyl (Ts) group.
- PNZ N-para- nitrobenzyloxycarbonyl
- Cbz Carbobenzyloxy
- Moz or MeOZ tert-Butyloxycarbonyl
- FMOC 9-Fluorenylmethyloxycarbonyl
- PMB 3,4-Dimethoxybenzyl
- PMPM 3,4-Dimethoxybenzyl
- PMP Tosyl
- P is N-tertiary-butyoxycarbonyl (N-boc).
- Y is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (also referred to herein as O-Ms, or CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf).
- Ts tosylate
- mesylate also referred to herein as O-Ms, or CH3S(0)3
- trifluoromethane sulfonate also referred to as triflate or OTf
- Y is chloro
- Y is bromo
- R is selected from the group consisting of Q.salkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C ⁇ alkyl, aryl, aryl C _ 4alkyl and heteroaryl C ⁇ alkyl.
- R is a Ci.galkyl, preferably a Ci_4alkyl, and more preferably a Ci_2alkyl.
- R is ethyl.
- the compounds of the present application are key intermediates in the synthesis of the compounds of Formula (I) as described in United States Patent Nos. 7,488,827 and 7,498,440
- Suitable organic solvents include THF, toluene, heptane, chloroform, acetonitrile. preferably THF, toluene, or heptane.
- P is a protecting group
- R is selected from the group consisting of Q.salkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C ⁇ alkyl, aryl, aryl C _
- Y is a leaving group
- P is a protecting group
- R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci_4alkyl, aryl, aryl Q_ 4alkyl and heteroaryl Ci_4alkyl; a solution of Base, wherein Base is a compound able to deprotonate a weakly acidic C-H bond; and
- step (b) adding to the solution of step (a) a compound of the formula:
- Y is a leaving group
- X is a leaving group; provided that X and Y are different; to yield a compound of Formula (II).
- P is selected from the group of nitrogen protecting groups consisting of N-para- nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), /?-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP) and Tosyl (Ts) group.
- PNZ N-para- nitrobenzyloxycarbonyl
- Cbz Carbobenzyloxy
- Moz or MeOZ tert-Butyloxycarbonyl
- FMOC 9-Fluorenylmethyloxycarbonyl
- PMB 3,4-Dimethoxybenzyl
- PMMP 3,4-Dimethoxybenzyl
- Ts Tosyl
- Y is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf).
- Ts halogen, tosylate
- CH3S(0)3 mesylate
- OTf trifluoromethane sulfonate
- Y is halogen. In one embodiment of the invention Y is chloro.
- Y is bromo
- X is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf).
- Ts halogen, tosylate
- CH3S(0)3 mesylate
- OTf trifluoromethane sulfonate
- X is halogen
- X is chloro. In one embodiment of the invention X is bromo.
- both X and Y are halogen. In another embodiment of the invention one of X and Y are chloro and the other is bromo.
- R is selected from the group consisting of Q.galkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C ⁇ alkyl, aryl, aryl C ⁇ alkyl and heteroaryl C ⁇ alkyl.
- R is a C ⁇ .galkyl, preferably a C ⁇ alkyl, and more preferably a C ⁇ alkyl.
- R is ethyl.
- Base is selected from potassium (KHMDS), lithium (LiHMDS) or sodium (NaHMDS) hexamethyldisilazide, lithium isopropylcyclohexylamine (LICA), lithium tetramethylpiperidine LiTMP, lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide (LDA), potassium t-butoxide (KOtBu), or sodium ethoxide (NaOEt).
- KHMDS potassium
- LiHMDS lithium
- NaHMDS sodium hexamethyldisilazide
- LDA lithium diisopropylamide
- KOEt potassium t-butoxide
- NaOEt sodium ethoxide
- LiTMP may be prepared by reacting tetramethylpiperidine and butyllithium, although this is a highly exothermic reaction.
- Base is selected from potassium (KHMDS), lithium (LiHMDS) or sodium (NaHMDS) hexamethyldisilazide, lithium isopropylcyclohexylamine (LICA), lithium tetramethylpiperidine LiTMP, lithium hexamethyldisilazide, or sodium hexamethyldisilazide.
- Base is lithium hexamethyldisilazide (LiHMDS). In another embodiment of the invention, Base is lithium hexamethyldisilazide (LiHMDS), and the solvent is toluene.
- the Base is lithium hexamethyldisilazide (LiHMDS), the solvent is toluene, the reaction temperature is at room temperature.
- LiHMDS lithium hexamethyldisilazide
- the solvent is toluene
- the reaction temperature is at room temperature.
- the reaction is carried out under room temperature to about 90 °C, preferably from about room temperature to about 60°C.
- Suitable organic solvents for use herein include THF, toluene, heptane, chloroform, or acetonitrile, preferably THF, toluene, or heptane.
- alkyl refers to a branched or straight chain hydrocarbon containing from 1 to 12 carbons, preferably 1 to 8 carbons, such as, methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like.
- alkenyl refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons with one or more double bonds in the chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3- nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like.
- alkynyl refers to straight or branched chain radicals of 2 to 12 carbons and preferably 2 to 8 carbons with one or more triple bonds in the normal chain, such as 2- propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4- dodecynyl and the like.
- cycloalkyl unless otherwise defined, by itself or as part of another group, includes a saturated or partially unsaturated (containing one or more double bonds) cyclic hydrocarbon group containing a total of 3 to 6 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
- heterocyclo refers to a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine.
- sulfur may be optionally oxidized to the sulfone or the sulfoxide.
- aryl unless otherwise defined, by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system containing 6 to 10 carbons in the ring portion (such as phenyl, 1-naphthyl and 2-naphthyl),
- heteroaryl unless otherwise defined, by itself or as part of another group refers to a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, indole or benzimidazole.
- halogen or "halo" unless otherwise defined, refers to chlorine, fluorine, iodine, and bromine.
- a “leaving group” as defined herein is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI “ , Br “ , ⁇ , and sulfonate esters, such as /?ara-toluenesulfonate or "tosylate” (TsO ).
- a “protecting group” as defined herein is a molecular entity that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. Common functional groups protected during organic synthesis by a “protecting group” are alcohols, amines, carbonyls, carboxylic acids and phosphates.
- a “base” as defined herein is a chemical compound that is able to deprotonate very weak acids in an acid-base reaction.
- Compounds with a pKa of more than about 13 are called strong bases.
- Very strong bases are even able to deprotonate very weakly acidic C-H groups in the absence of water.
- amino protected starting material as defined herein is a chemical compound that is commercially available wherein the amine group is protected by a protecting group useful in organic synthesis.
- Examples 1-7 are synthetic methods for preparing ethyl-4-(2-chloroethyl)-N-boc- piperidine-4-carboxylate from ethyl-N-boc-piperidine-4-carboxylate.
- the examples differ by choice of base, solvent and reaction conditions.
- Examples 2-7 were performed by the method described in Example 1. The specific base, solvent, reaction temperature and percent yield are reported below.
- Ethyl-4-(2-chloroethyl)-N-boc-piperidine-4-carboxylate (lOOmg) was dissolved in 4M HC1 in dioxane (2.5mL) at room temperature. After 1 hour, LC-MS analysis showed 73% a/a conversion to the Ethyl-4-(2-chloroethyl)-piperidine-4-carboxylate. Evaporation of the reaction mixture, confirmed the structure of the product, in a 73% yield.
Abstract
The present application describes novel intermediates useful in the synthesis of mAChRs and methods for preparing these intermediates, comprising a compound of Formula (II): wherein, P is a suitably nitrogen protecting group; R is selected from the group consisting of C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, heterocyclic, heterocyclic C1-4alkyl, aryl, aryl C1-4alkyl and heteroaryl C1-4alkyl; and Y is a suitable leaving group.
Description
METHODS OF PREPARATION OF MUSCARINIC ACETYLCHOLINE
RECEPTOR ANTAGONISTS
FIELD OF INVENTION
The present application relates to the fields of organic synthesis, and pharmaceutical process chemistry. In particular, the inventive concept relates to the synthesis of key intermediates useful in the preparation of Muscarinic Acetylcholine Receptor Antagonists (hereinafter "mAChRs") useful in the treatment of various respiratory diseases and disorders.
BACKGROUND OF THE INVENTION
A series of mAChRs according to Formula (I), pharmaceutical compositions containing the mAChRs of Formula (I) and methods of treatment using the mAChRs of Formula (I) are described in WO 2005/104745, and United States Patent Nos. 7,488,827 and 7,498,440
(I)
wherein:
interalia,
Rl is selected from the group consisting of Cl-15 alkyl, halosubstituted Cl-15 alkyl, Cl-15 alkyl cycloalkyl, cycloalkyl, C2-15 alkenyl, hydroxy substituted Cl-15 alkyl, Cl-15 alkyl aryl, Cl-15 alkyl heteroaryl, (CR7R7)qNRaRa, (CR7R7)qNC(0)Ra, (CR7R7)qC(0)NRaRa, (CR7R7)qC(0)Ra, (CR7R7)qOC (O)Ra,
R2 and R3 are independently selected from the group consisting of aryl, CI -4 alkyl aryl, heteroaryl, CI -4 alkyl heteroaryl, heterocyclic and a CI -4 alkyl heterocyclic moiety, all of which moieties may be optionally substituted; and
X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
The process of manufacturing the mAChRs according to Formula (I) in WO 2005/104745, United States Patent Nos. 7,488,827 and 7,498,440 is outlined below in Scheme I:
Reagents and conditions: a) l-bromo-2-chloroethane, K2C03, acetone; b) LDA, THF; c) R2M then R M, THF; d) R1X, ACN, CHC13.
In Example 1 of WO 2005/104745, United States Patent Nos. 7,488,827 and 7,498,440 Ethyl l-(2-chloroethyl)-4-piperidinecarboxylate is prepared by adding l-bromo-2- chloroethane to a solution of commercially available ethyl nipecotate, in acetone, followed by addition of potassium carbonate. This synthesis is illustrated below as Scheme B:
Example 1 produced a 38.6% yield of the desired Ethyl l-(2-chloroethyl)-4- piperidinecarboxylate product.
As this is the first step in a multi-step organic synthesis it is desirable to develop an alternative synthesis that utilizes commercially available starting material and results in a higher percentage yield. In addition, ethyl l-(2-chloroethyl)-4-piperidinecarboxylate is a highly toxic intermediate. It is therefore also desirable to identify an alternative synthetic route to avoid formation of this toxic intermediate.
SUMMARY OF THE INVENTION
This application relates to intermediates according to Formula (II)
C wherein,
P is a protecting group;
R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl;
Y is a leaving group.
Another embodiment of the invention is a process of making compounds of Formula (II)
wherein,
P is a protecting group;
R is selected from the group consisting of Q.galkyl, C2-galkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci^alkyl, aryl, aryl C _
4alkyl and heteroaryl C^alkyl; and
Y is a leaving group;
comprising;
(a) adding to a solution of a compound according to Formula (III):
wherein,
P is a protecting group; and
R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Q^alkyl, aryl, aryl C i_4alkyl and heteroaryl C i_4alkyl;
a solution of Base, wherein Base is a compound able to deprotonate a weakly acidic C-H bond; and
wherein
Y is a leaving group; and
X is a leaving group; provided that X and Y are different; to yield a compound of Formula (II).
DETAILED DESCRIPTION OF THE INVENTION
The present application relates to novel compounds useful as key intermediates in the synthesis of mAChRs as described in WO 2005/104745, which is incorporated by reference herein, and novel methods of preparing these key intermediates.
In one embodiment of the present application there are provided novel compounds according to Formula (II):
(Π)
wherein,
P is a protecting group;
R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci_4alkyl, aryl, aryl Q_ 4alkyl and heteroaryl Ci_4alkyl; and
Y is a leaving group.
Suitably P is selected from the group of nitrogen protecting groups consisting of N-para- nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), /?-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP) and Tosyl (Ts) group.
In one embodiment of the invention P is N-tertiary-butyoxycarbonyl (N-boc).
Suitably, Y is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (also referred to herein as O-Ms, or CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf). In embodiment of the invention Y is halogen.
In one embodiment of the invention Y is chloro.
In one embodiment of the invention Y is bromo.
Suitably, R is selected from the group consisting of Q.salkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^alkyl, aryl, aryl C _ 4alkyl and heteroaryl C^alkyl.
In one embodiment of the invention R is a Ci.galkyl, preferably a Ci_4alkyl, and more preferably a Ci_2alkyl.
One embodiment of the invention is where R is ethyl.
The compounds of the present application are key intermediates in the synthesis of the compounds of Formula (I) as described in United States Patent Nos. 7,488,827 and 7,498,440
A general synthetic scheme using the compounds of the present invention to synth compounds of Formula (I) is illustrated in Scheme II below:
Scheme II
Intermediates useful in the preparation of mAChRs may be prepared generally according to Scheme III a hown below:
(I I I) (I I)
Scheme III
A solution of commercially available amino protected starting material (Formula III as defined herein) in a suitable organic solvent is added slowly to a suitable Base (as defined herein) under nitrogen atmosphere. The reaction mixture is left to mix for a period of about 10 minutes to about 2 hours. If desired, two samples at 10 minute intervals are taken and quenched in deuterated methanol for LCMS analysis to check for the deprotonation of the starting material. Next a compound with two leaving groups (X-
CH2- CH2-Y) is added to the reaction mixture. Samples for LCMS and !Η NMR analysis are taken regularly to check for the formation of product compared to the levels of starting material, compound with two leaving groups and various impurities.
Suitable organic solvents include THF, toluene, heptane, chloroform, acetonitrile. preferably THF, toluene, or heptane.
(IV)
Scheme IV
A solution of the commercially available piperidine compound (a compound of Formula IV, wherein R is as defined for a compound of Formula III), in an organic solvent is added slowly to a base and a suitable protecting group, under nitrogen atmosphere.
Thus, in a second embodiment of the present application there are provided methods for preparing a compound of Formula (II):
wherein,
P is a protecting group;
R is selected from the group consisting of Q.salkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^alkyl, aryl, aryl C _
4alkyl and heteroaryl C^alkyl; and
Y is a leaving group;
which method comprises
adding to a solution of a compound according to Formula (III), in an organic solvent:
wherein,
P is a protecting group; and
R is selected from the group consisting of Q.galkyl, C2-8alkenyl, C2-8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic Ci_4alkyl, aryl, aryl Q_ 4alkyl and heteroaryl Ci_4alkyl; a solution of Base, wherein Base is a compound able to deprotonate a weakly acidic C-H bond; and
(b) adding to the solution of step (a) a compound of the formula:
X
wherein
Y is a leaving group; and
X is a leaving group; provided that X and Y are different; to yield a compound of Formula (II).
Suitably P is selected from the group of nitrogen protecting groups consisting of N-para- nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), /?-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP) and Tosyl (Ts) group.
In one embodiment of the invention P is N-tertiary-butyoxycarbonyl (N-boc).
Suitably, Y is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf).
In embodiment of the invention Y is halogen. In one embodiment of the invention Y is chloro.
In one embodiment of the invention Y is bromo.
Suitably, X is a leaving group such as a halogen, tosylate (also referred to herein as Ts), mesylate (CH3S(0)3 ), or trifluoromethane sulfonate (also referred to as triflate or OTf).
In one embodiment of the invention X is halogen.
In one embodiment of the invention X is chloro. In one embodiment of the invention X is bromo.
In one embodiment of the invention both X and Y are halogen. In another embodiment of the invention one of X and Y are chloro and the other is bromo. Suitably, R is selected from the group consisting of Q.galkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^alkyl, aryl, aryl C^alkyl and heteroaryl C^alkyl.
In one embodiment of the invention R is a C^.galkyl, preferably a C^alkyl, and more preferably a C^alkyl.
One embodiment of the invention is where R is ethyl.
Suitably, Base is selected from potassium (KHMDS), lithium (LiHMDS) or sodium (NaHMDS) hexamethyldisilazide, lithium isopropylcyclohexylamine (LICA), lithium tetramethylpiperidine LiTMP, lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide (LDA), potassium t-butoxide (KOtBu), or sodium ethoxide (NaOEt). Although Base when potassium t-butoxide (KOtBu), or sodium ethoxide (NaOEt) was used under room temperature conditions, with THF as a solvent did not produce a compound of Formula (II), it is possible under elevated conditions that conversion may be possible.
LiTMP may be prepared by reacting tetramethylpiperidine and butyllithium, although this is a highly exothermic reaction.
In one embodiment of the invention, Base is selected from potassium (KHMDS), lithium (LiHMDS) or sodium (NaHMDS) hexamethyldisilazide, lithium isopropylcyclohexylamine (LICA), lithium tetramethylpiperidine LiTMP, lithium hexamethyldisilazide, or sodium hexamethyldisilazide.
In one embodiment of the invention Base is lithium hexamethyldisilazide (LiHMDS). In another embodiment of the invention, Base is lithium hexamethyldisilazide (LiHMDS), and the solvent is toluene.
In another embodiment of the invention, the Base is lithium hexamethyldisilazide (LiHMDS), the solvent is toluene, the reaction temperature is at room temperature.
Suitably, the reaction is carried out under room temperature to about 90 °C, preferably from about room temperature to about 60°C.
Suitable organic solvents for use herein include THF, toluene, heptane, chloroform, or acetonitrile, preferably THF, toluene, or heptane.
Definitions
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term "alkyl", unless otherwise defined, by itself or as part of another group, refers to a branched or straight chain hydrocarbon containing from 1 to 12 carbons, preferably 1 to 8 carbons, such as, methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like.
As used herein, the term "alkenyl", unless otherwise defined, refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons with one or more double bonds in the chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3- nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like.
As used herein the term "alkynyl", unless otherwise defined, by itself or as part of another group, refers to straight or branched chain radicals of 2 to 12 carbons and preferably 2 to 8 carbons with one or more triple bonds in the normal chain, such as 2- propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4- dodecynyl and the like. As used herein the term "cycloalkyl", unless otherwise defined, by itself or as part of another group, includes a saturated or partially unsaturated (containing one or more double bonds) cyclic hydrocarbon group containing a total of 3 to 6 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein the terms "heterocyclo", "heterocycle", "heterocyclyl" or "heterocyclic ring", unless otherwise defined, refers to a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms
selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfur may be optionally oxidized to the sulfone or the sulfoxide. As used herein the term "aryl", unless otherwise defined, by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system containing 6 to 10 carbons in the ring portion (such as phenyl, 1-naphthyl and 2-naphthyl),
As used herein the term "heteroaryl" unless otherwise defined, by itself or as part of another group refers to a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, indole or benzimidazole.
As used herein the term "halogen" or "halo" unless otherwise defined, refers to chlorine, fluorine, iodine, and bromine.
A "leaving group" as defined herein is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI", Br", Γ, and sulfonate esters, such as /?ara-toluenesulfonate or "tosylate" (TsO ).
A "protecting group" as defined herein is a molecular entity that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. Common functional groups protected during organic synthesis by a "protecting group" are alcohols, amines, carbonyls, carboxylic acids and phosphates.
A "base" as defined herein is a chemical compound that is able to deprotonate very weak acids in an acid-base reaction. Compounds with a pKa of more than about 13 are called
strong bases. Very strong bases are even able to deprotonate very weakly acidic C-H groups in the absence of water.
An "amino protected starting material" as defined herein is a chemical compound that is commercially available wherein the amine group is protected by a protecting group useful in organic synthesis.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
Methods of Preparation
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity.
Liquid Chromatograph
System: Shimadzu LC system with SCL-IOA Controller and dual UV detector
Autosampler: Leap CTC with a Valco six port injector
Column: Aquasil/Aquasil (CI 8 40x1 mm)
Inj. Vol.(uL): 2.0
Solvent A: H20, 0.02% TFA
Solvent B: MeCN, 0.018% TFA
Gradient: linear
Channel A: UV 214 nm
Channel B: ELS
Step Time (min) Dura.(min) Flow (μΕ/ηιίη) SoLA Sol.B
0 0.00 0.00 300.00 95.00 5.00
1 0.00 0.01 300.00 95.00 5.00
2 0.01 3.20 300.00 10.00 90.00
3 3.21 1.00 300.00 10.00 90.00
4 4.21 0.10 300.00 95.00 5.00
5 4.31 0.40 300.00 95.00 5.00
Mass Spectrometer: PE Sciex Single Quadrupole LC/MS API-150
Polarity: Positive
Acquisition mode: Profile General Procedures Nuclear magnetic resonance spectra were recorded at 400 MHz using on Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD (or MeOD) is tetradeuteriomethanol.
Chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Mass spectra were taken on a instruments, using electrospray (ES) ionization techniques. All temperatures are reported in degrees Celsius. All other abbreviations are as described in the ACS Style Guide (American Chemical Society, Washington, DC, 1986).
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Preparative hplc were performed using a Gilson Preparative System using a Luna 5u CI 8(2) 100A reverse phase column eluting with a 10-80 gradient (0.1%TFA in acetonitrile/0.1% aqueous TFA) or a 10-80 gradient (acetonitrile/water). The CombiFlash system used for purification in this application was
purchased from Isco, Inc. CombiFlash purification was carried out using a prepacked S1O2 column, a detector with UV wavelength at 254nm and mixed solvents.
EXAMPLES
Examples 1-7 are synthetic methods for preparing ethyl-4-(2-chloroethyl)-N-boc- piperidine-4-carboxylate from ethyl-N-boc-piperidine-4-carboxylate. The examples differ by choice of base, solvent and reaction conditions.
Example 1
Ethyl-4-(2-chloroethyl)-N-boc-piperidine-4-carboxylate
All quantities are equivalent to ethyl N-Boc-piperidine-4-carboxylate. A solution of ethyl N-Boc-piperidine-4-carboxylate (4.68g, 1 equivalent) in anhydrous toluene, was added over 50 minutes to a solution of 1M lithium hexamethyldisilazide in toluene (20mL, 1.10 equivalents) which had been heated in a bath set to 50°C. l-bromo-2- chloroethane (1.6mL, 1.05 equivalents) was added to the reaction mixture. The heating bath was heated to 70°C, then 90°C and samples were taken regularly for LC-MS analysis. Several hours after the addition of l-bromo-2-chloroethane, the reaction mixture was allowed to cool to room temperature and was left to stand overnight. The following morning, ethanol (1.25mL), followed by water was added (35mL) and the biphase was stirred. The aqueous phase was discarded and the organic layer was washed with 15%wt brine solution (lOmL). The aqueous phase was discarded and the organic layer was evaporated to give an orange oil (4.68g). 4.14g of this orange oil was dissolved in the minimum amount of dichloromethane and was loaded onto a 340g silica column, which was eluted with 2.4% ethyl acetate in dichloromethane over 1 column volume, followed by 2.4% to 20% ethyl acetate in dichloromethane over 10 column volumes and
then 20% ethyl acetate in dichloromethane over 2 column volumes. 30 fractions of 120mL were collected and the fractions containing product were combined and concentrated to give a colourless oil (1.41g, 19.9%). 1H NMR and LC-MS analysis showed data which was concordant with the desired product. 1H NMR (CD3OD , 400 MHz) δ 4.11 (q, J=7.1Hz, 2H), 3.76 (m 2H), 3.41 (dd, 2H), 2.82 (broad s, 2H), 2.01 (m, 2H), 1.94 (dd, J = 7.9Hz, 2H), 1.35 - 1.28 (m, 1 1H), 1.18 (t, J = 7.1Hz, 3H). LC-MS, the isolated product has a retention time of 5.86 minutes and a MH+ of 320.
Examples 2-7
Examples 2-7 were performed by the method described in Example 1. The specific base, solvent, reaction temperature and percent yield are reported below.
Reference Example 8
Deprotection of Ethyl-4-(2-chloroethyl)-N-boc-piperidine-4-carboxylate
Ethyl-4-(2-chloroethyl)-N-boc-piperidine-4-carboxylate (lOOmg) was dissolved in 4M HC1 in dioxane (2.5mL) at room temperature. After 1 hour, LC-MS analysis showed 73% a/a conversion to the Ethyl-4-(2-chloroethyl)-piperidine-4-carboxylate. Evaporation of the reaction mixture, confirmed the structure of the product, in a 73% yield.
Reference Example 9
Ethyl-l-azabicyclo [2.2.21 octane -4-carboxylate
Ethyl-4-(2-chloroethyl)-piperidine-4-carboxylate (80mg), toluene (10ml) and fine potassium carbonate (0.5g) were stirred at reflux for 1 hour. LC-MS showed the reaction was complete. The solids were filtered and washed with toluene. The filtrate was evaporated to give an oil. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.
Claims
1. A compound according to Formula (II):
(Π) wherein,
P is a protecting group;
R is selected from the group consisting of Q.galkyl, C2_8alkenyl, C2_8alkynyl,
C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^alkyl, aryl, aryl C\_
4alkyl and heteroaryl C^alkyl; and
Y is a leaving group.
2. The compound according to Claim 1 , wherein P is selected from the group of nitrogen protecting groups consisting of N-para-nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), -Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP), ethoxybenzyl and Tosyl (Ts) group.
3. The compound according to Claim 2, wherein P is tert-Butyloxycarbonyl
(BOC).
4. The compound according to Claim 1, wherein Y is a leaving group selected from the group consisting of halogen, tosylate, mesylate and triflate.
5. The compound according to Claim 4, wherein Y is halogen.
6. The compound according to Claim 5, wherein Y is chloro.
7. The compound according to Claim 1, wherein R is C^alkyl.
8. The compound according to Claim 7, wherein R is methyl or ethyl.
9. The compound according to Claim 1, wherein R is methyl or ethyl, Y is chloro or bromo and P is tert-Butyloxycarbonyl (BOC).
10. A process for the preparation of a compound of Formula (II):
(Π)
wherein,
P is a protecting group;
R is selected from the group consisting of Q.galkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^^alkyl, aryl, aryl C _
4alkyl and heteroaryl C^alkyl; and
Y is a leaving group;
comprising; a) adding to a solution of Base, wherein Base is a compound able to deprotonate a weakly acidic C-H bond; a solution of a compound according to Formula (III), in an organic solvent:
wherein,
P is a protecting group; and
R is selected from the group consisting of Q.salkyl, C2_8alkenyl, C2_8alkynyl, C3_6cycloalkyl, C3_6cycloalkenyl, heterocycle, heterocyclic C^alkyl, aryl, aryl C _ 4alkyl and heteroaryl C^alkyl; and
(b) adding to the mixture of step (a) a compound of the formula:
Y
X
wherein
Y is a leaving group; and
X is a leaving group; provided that X and Y are different; to yield a compound of Formula (II).
11. The process according to Claim 10, wherein P is selected from the group of nitrogen protecting group consisting of N-para-nitrobenzyloxycarbonyl (PNZ), Carbobenzyloxy (Cbz), /?-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), /?-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and /?-methoxyphenyl (PMP), ethoxybenzyl and Tosyl (Ts) group.
12. The process according to Claim 11, wherein P is N-tertiary- butyoxycarbonyl (N-boc).
13. The process according to Claim 10 or 11, wherein X is a leaving group selected from the group consisting of halogen, tosylate, mesylate and triflate.
halogen.
14. The process according to Claim 13, wherein X is halogen.
15. The process according to Claim 14, wherein X is bromo.
16. The process according to any one of Claims 10 to 15, wherein Y is a leaving group selected from the group consisting of halogen, tosylate, mesylate and trifilate.
17. The process according to Claim 16, wherein Y is halogen.
18. The process according to Claim 17, Y is chloro.
19. The process according to Claim 10, wherein R is a C^alkyl.
20. The process according to Claim 19, R is methyl or ethyl.
21. The process according to any one of Claim 10 to 20, wherein Base is selected from the group consisting of potassium hexamethyldisilazide, lithium isopropylcyclohexylamine, lithium tetramethylpiperidine, lithium hexamethyldisilazide and sodium hexamethyldisilazide.
22. The process according to Claim 21, wherein Base is lithium hexamethyldisilazide.
23. The process according to any of Claims 10 to 22 wherein the organic solvent is selected from THF, toluene, heptane, chloroform, or acetonitrile.
24. The process according to Claim 23 wherein the organic solvent is selected from THF, toluene, or heptane.
25. The process according to any of Claims 10 to 24 wherein the reaction is carried out at about room temperature to about 90°C.
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